Phase-dependent modulation of the vestibular–cerebellar network via combined alternating current stimulation influences human locomotion and posture

BackgroundHuman locomotion induces rhythmic movements of the trunk and head. Vestibular signaling is relayed to multiple regions in the brainstem and cerebellum, and plays an essential role in maintaining head stability. However, how the vestibular–cerebellar network contributes to the rhythmic locomotor pattern in humans is unclear. Transcranial alternating current stimulation (tACS) has been used to investigate the effects of the task-related network between stimulation regions in a phase-dependent manner. Here, we investigated the relationship between the vestibular system and the cerebellum during walking imagery using combined tACS over the left cerebellum and alternating current galvanic vestibular stimulation (AC-GVS).MethodsIn Experiment 1, we tested the effects of AC-GVS alone at around individual gait stride frequencies. In Experiment 2, we then determined the phase-specificity of combined stimulation at the gait frequency. Combined stimulation was applied at in-phase (0° phase lag) or anti-phase (180° phase lag) between the left vestibular and left cerebellar stimulation, and the sham stimulation. We evaluated the AC-GVS-induced periodic postural response during walking imagery or no-imagery using the peak oscillatory power on the angular velocity signals of the head in both experiments. In Experiment 2, we also examined the phase-locking value (PLV) between the periodic postural responses and the left AC-GVS signals to estimate entrainment of the postural response by AC-GVS.ResultsAC-GVS alone induced the periodic postural response in the yaw and roll axes, but no interactions with imagery walking were observed in Experiment 1 (p > 0.05). By contrast, combined in-phase stimulation increased yaw motion (0.345 ± 0.23) compared with sham (−0.044 ± 0.19) and anti-phase stimulation (−0.066 ± 0.18) during imaginary walking (in-phase vs. other conditions, imagery: p < 0.05; no-imagery: p ≥ 0.125). Furthermore, there was a positive correlation between the yaw peak power of actual locomotion and in-phase stimulation in the imagery session (imagery: p = 0.041; no-imagery: p = 0.177). Meanwhile, we found no imagery-dependent effects in roll peak power or PLV, although in-phase stimulation enhanced roll motion and PLV in Experiment 2.ConclusionThese findings suggest that combined stimulation can influence vestibular–cerebellar network activity, and modulate postural control and locomotion systems in a temporally sensitive manner. This novel combined tACS/AC-GVS stimulation approach may advance development of therapeutic applications

Generation of medaka gene knockout models by target-selected mutagenesis

We have established a reverse genetics approach for the routine generation of medaka (Oryzias latipes) gene knockouts. A cryopreserved library of N-ethyl-N-nitrosourea (ENU) mutagenized fish was screened by high-throughput resequencing for induced point mutations. Nonsense and splice site mutations were retrieved for the Blm, Sirt1, Parkin and p53 genes and functional characterization of p53 mutants indicated a complete knockout of p53 function. The current cryopreserved resource is expected to contain knockouts for most medaka genes

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target